Neoantigen landscape dynamics during human melanoma-T cell interactions

Els M. E. Verdegaal, Noel F. C. C. De Miranda, Marten Visser, Tom Harryvan, Marit M. Van Buuren, Rikke Sølbeck Andersen, Sine Reker Hadrup, Caroline E. Van Der Minne, Remko Schotte, Hergen Spits, John B. A. G. Haanen, Ellen H. W. Kapiteijn, Ton N. Schumacher, Sjoerd H. Van Der Burg

    Research output: Contribution to journalLetterpeer-review

    Abstract

    Recognition of neoantigens that are formed as a consequence of DNA damage is likely to form a major driving force behind the clinical activity of cancer immunotherapies such as T-cell checkpoint blockade and adoptive T-cell therapy. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens are currently under development. In mouse models, T-cell pressure can sculpt the antigenicity of tumours, resulting in the emergence of tumours that lack defined mutant antigens. However, whether the T-cell-recognized neoantigen repertoire in human cancers is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer cells and T cells, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance.
    Original languageEnglish
    JournalNature
    Volume536
    Issue number7614
    Pages (from-to)91-95
    Number of pages5
    ISSN0028-0836
    DOIs
    Publication statusPublished - 2016

    Keywords

    • Medicine (all)
    • Multidisciplinary

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